Using direct intraneural recordings (microneurography) of muscle sympathetic nerve activity (MSNA) in humans, we have recently provided new insight into mechanisms of autonomic adjustments to exercise in humans. This work has demonstrated that: 1) there is differential control of heart rate and MSNA, 2) central command and muscle afferents produce strikingly different autonomic responses and 3) chemosensitive muscle afferents increase whereas central command inhibits MSNA. I propose to extend this work to an evaluation of factors which modulate sympathetic nerve responses to static and dynamic exercise in humans. First, I will test the hypothesis that bradykinin is a stimulus to the somatic pressor reflex by determining if inhibition of kininase II with captopril selectively augments MSNA responses to sustained handgrip without augmenting responses to other reflex stimuli. Second, we have recently demonstrated that acute administration of propranolol potentiates increases in MSNA during sustained handgrip. I plan to determine if this results from blockade of beta-1 receptors (decreased cardiac baroreflex modulation of somatic pressor reflex) or beta-2 receptors (increased potassium efflux from contracting muscle) and whether this potentiation is seen with chronic as well as acute beta blockade. Third, I plan to measure MSNA in the arm (median nerve) and leg (peroneal nerve) to determine if sustained handgrip inhibits MSNA in the arm while stimulating MSNA in the leg. Our previous work indicates that sustained handgrip increases MSNA in the leg, but we propose that the sympathoinhibitory influence of central command may be greater in the arm and override increases in MSNA. Fourth, I will test the hypothesis that the fall in blood pressure after a bout of prolonged dynamic exercise is associated with a reduction of MSNA and that the decrease in MSNA is reversed by naloxone, thus implicating endogenous opiods. The distinctive features of this research include: 1) direct recordings of MSNA in humans using a safe, reproducible and quantitative method and 2) the pursuit of basic mechanisms of neurogenic control in human subjects.